Heart disease remains the leading cause of death in this country and, for the first time in 30 years, the Centers for Disease Control and Prevention reported that cardiac-related deaths are on the rise. A primary contributor to these numbers is hypertensive heart disease, which is characterized by myocyte hypertrophy and widespread fibrosis. Fibrotic remodeling increases both cardiac arrhythmogenicity and myocardial stiffness that cause a rapid progression toward failure. Thus, decades of research have been directed toward identifying the basis for cardiac remodeling with an eye toward short circuiting this maladaptive process. In doing so, the field has largely focused on cardiac myocytes, but the recent emergence of targeted genetic approaches for manipulating cardiac cells has revealed vital roles for nonmyocytes in mediating cardiac plasticity. Fibroblasts have gained traction in this respect, as demonstrated by the surge of evidence shifting their role from a passive player responding to cardiac myocyte dysfunction to a primary component of the disease process.1,2

Building on this theme, the findings from Li et al,3 which are featured in this issue of Circulation, underscore the importance of revisiting previously defined remodeling signals in a more targeted cellular context. This study was focused on uncovering new transcriptional mechanisms for cardiac remodeling, and with RNAseq analysis they identified 22 transcription factors that were differentially expressed in whole heart lysates from 2 independent mouse models of hypertensive heart disease: chronic angiotensin II (AngII) infusion and pressure overload (transverse aortic constriction). Within this overlapping subgroup, activating transcription factor 3 (ATF3) had the greatest increase in expression and was the most consistently upregulated of the 22 candidate factors. ATF3 has long been identified as a global stress-response mechanism because it is rarely expressed in healthy tissues, but is induced by a wide …